Combined tyrosine and serine/threonine kinase inhibition by sorafenib prevents progression of experimental pulmonary hypertension and myocardial remodeling.
BACKGROUND
Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension.


RESULTS
We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (n=12 to 16 per group). RV systolic pressure was decreased to 35.0+/-1.5 mm Hg by sorafenib and to 54.0+/-4.4 mm Hg by imatinib compared with placebo (82.9+/-6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2.


CONCLUSIONS
The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling.
Klein
Martina
M
Cardiology Research, Bayer Schering Pharma, Wuppertal, Germany.
Schermuly
Ralph T
RT
Ellinghaus
Peter
P
Milting
Hendrik
H
Riedl
Bernd
B
Nikolova
Sevdalina
S
Pullamsetti
Soni S
SS
Weissmann
Norbert
N
Dony
Eva
E
Savai
Rajkumar
R
Ghofrani
Hossein A
HA
Grimminger
Friedrich
F
Busch
Andreas E
AE
Schäfer
Stefan
S
D000818:Animals; D001549:Benzamides; D001557:Benzenesulfonates / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006352:Heart Ventricles; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000068877:Imatinib Mesylate; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D020257:Ventricular Remodeling / Q000187:drug effects*; D048490:raf Kinases / Q000037:antagonists & inhibitors*
D001549:Benzamides; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D009536:Niacinamide; D000068877:Imatinib Mesylate; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases